The health of the people and the economy of the United States of America remain under siege from obesity. Nutrient intake is an important variable in the control of body weight and its dysregulation can lead to obesity. Numerous afferent stimuli, including hormones both old and new, have been implicated in the nutritional and metabolic regulation of body weight, but the neurochemical basis for their integration remains elusive. A newly recognized neurotransmitter, nitric oxide, has been implicated in the neurochemical regulation of various central nervous system processes, including the ingestion of food and water. There is evidence, derived from the observation that inhibitors of nitric oxide synthase oppose the hyperphagia caused by many disparate stimuli, to suggest that the locus of action of nitric oxide may be distal to the level of many of the transmitter-receptor systems in the hypothalamus which play a role in the regulation of food intake. This grant is focused on the further evaluation of the contribution of this neurotransmitter to the control of body weight and to test the overall hypothesis that nitric oxide is a common downstream effector linking and intergrating multiple diverse stimuli with increased food intake. Specific aims are to directly inject, into the brain of rats, substances known to increase or decrease the concentration of nitric oxide and to correlate changes in food ingestion and body weight with histochemical and biochemical alterations in the levels of protein and gene expression, catalytic activity and product of the enzymes responsible for the synthesis of nitric oxide. Because nitric oxide contributes to the regulation of many central nervous system processes, specificity will be increased by focusing on the areas which are activated to express the Fos protein in response to stimuli which regulate food intake. The secondary hypothesis is that alterations in this nitric oxide-dependent pathway may account for the prolonged and marked anorectic effect of cobalt protoporphyrin, a synthetic analogue of heme, which leads to profound and sustained weight loss. Experiments to test this secondary hypothesis will be carried out in addition to experiments to examine the molecular mechanism of these actions of cobalt protoporphyrin. This approach is expected to further our understanding of the physiology of appetite and body weight regulation in the central nervous system and eventually may assist in the development of strategies to combat the epidemic of obesity in western societies.